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ADAMTS20 ( A   d isintegrin-like  a nd  m etalloprotease domain with  t hrombo s pondin type-1 motifs) is a member of a family of secreted metalloproteases that can process a variety of extracellular matrix (ECM) components and secreted molecules.  Adamts20  mutations in  belted  ( bt ) mice cause white spotting of the dorsal and ventral torso, indicative of defective neural crest (NC)-derived melanoblast development. The expression pattern of  Adamts20  in dermal mesenchymal cells adjacent to migrating melanoblasts led us to initially propose that  Adamts20  regulated melanoblast migration. However, using a  Dct -LacZ transgene to track melanoblast development, we determined that melanoblasts were distributed normally in whole mount E12.5  bt/bt  embryos, but were specifically reduced in the trunk of E13.5  bt/bt  embryos due to a seven-fold higher rate of apoptosis. The melanoblast defect was exacerbated in newborn skin and embryos from  bt/bt  animals that were also haploinsufficient for  Adamts9 , a close homolog of  Adamts20 , indicating that these metalloproteases functionally overlap in melanoblast development. We identified two potential mechanisms by which  Adamts20  may regulate melanoblast survival. First, skin explant cultures demonstrated that  Adamts20  was required for melanoblasts to respond to soluble Kit ligand (sKitl). In support of this requirement,  bt/bt;Kit tm1Alf  /+ and  bt/bt;Kitl Sl  /+ mice exhibited synergistically increased spotting. Second, ADAMTS20 cleaved the aggregating proteoglycan versican  in vitro  and was necessary for versican processing  in vivo , raising the possibility that versican can participate in melanoblast development. These findings reveal previously unrecognized roles for  Adamts  proteases in cell survival and in mediating Kit signaling during melanoblast colonization of the skin. Our results have implications not only for understanding mechanisms of NC-derived melanoblast development but also provide insights on novel biological functions of secreted metalloproteases.

The Secreted Metalloprotease ADAMTS20 Is Required for Melanoblast Survival